Pleural fluid (PF) is a thin layer of fluid in the pleural cavity which serves as an important physiological lubricant and mechanical barrier. The volume and flow of PF are tightly regulated. In disease states, the dynamic of PF flow is compromised, resulting in abnormal accumulation of PF. This condition is called pleural effusion.
In clinical practice, the first step in investigating the etiology of pleural effusion is typically to classify PF as exudative (high protein) or transudative (low protein). This classification is used to narrow down the differential diagnosis (i.e., etiology) of the underlying causes. For example, causes for exudative pleural effusion include lung cancer (primary or secondary), infections (pulmonary tuberculosis, non-tuberculosis pneumonia or empyema) and autoimmune disease, while causes for transudative pleural effusion include congestive heart failure, chronic kidney disease and liver cirrhosis.
PF can be classified into exudate and transudate according to Light's criteria (Light, et al., Ann Intern Med., 77(4):507-513 (1972)). Briefly, Light, et al., performed a prospective study involving 150 pleural fluid samples, 47 transudates and 103 exudates and concluded that the presence of any one of the following features is highly suggestive of exudative pleural effusion: (1) the ratio of pleural fluid protein to serum protein is greater than 0.5; (2) a pleural fluid LDH is greater than 200 IU; or (3) the ratio of pleural fluid LDH to serum LDH is greater than 0.6. This set of criteria had been applied clinically for more than 40 years.
However, Porcel summarized the diagnostic accuracy of Light's criteria from 2115 subjects and reported a sensitivity ranged from 96.7% to 98.2% and specificity ranged from 69.4 to 77.7% (Porcel, Respirology, 16(1):44-52 (2011)). Other prospective studies have reported an even lower diagnostic specificity of 65-86%. The non-specificity of Light's criteria can cause misclassifications of PF. For example, transudative PF can be misdiagnosed as exudative PF, resulting in unnecessary testing and treatment of the subject. In a study involving 249 patients, classification of transudates based on clinical presentation could generate a misclassification rate of 42-44% (Romero-Candeira, et al., Chest, 122(5):1524-9 (2002)).
To enhance the diagnostic accuracy of PF classification, other biochemical markers/methods were considered in the laboratory evaluation of PF. For example, albumin gradient, NT-pro-BNP, BNP (Valdes, et al., Arch Bronconeumol., 47(5):246-51 (2011), C-reactive protein (CRP) (Porcel, et al., Eur. J. Intern. Med., 23(5):447-50 (2012)), cell counts (both red blood cells and white blood cells), glucose concentration, pH value, adenosine deaminase (ADA) activity (Chen, et al, Clin. Chim. Acta., 341(1-2):101-7 (2004), amylase, cholesterol (Vaz, et al., Curr. Opin. Pulm. Med., 7(4):183-6 (2001), Valdes, et al., Transl. Res., 155(4):178-84)), triglyceride (Valdes, et al, Lung, 188(6):483-9 (2010)), cell-free DNA (Chan, et al., Clin Chem., 49(5):740-5 (2003)), protein zone electrophoresis (Chen and Lam, Clin Chem., 45(10):1882-5 (1999)) among others. However, none of these tests can achieve both a sensitivity and specificity greater than 90%. Currently, there is no single marker that has both satisfactory sensitivity and specificity. Most of the markers have high sensitivity at the sacrifice of its specificity or vice versa.
Therefore, it is an object of the invention to provide methods for classifying pleural fluid as a transudate or an exudate with both high sensitivity and specificity.
It is a further object of the invention to provide methods of diagnosis and treatment including classification of pleural fluid as a transudate or an exudate with both high sensitivity and specificity.